#74 EEM

SYNTHESIS: To a solution of 12.3 g 3-ethoxy-4-methoxyphenol (see
recipe for MEM for the preparation of this phenol) in 20 mL MeOH,
there was added a warm solution of 4.8 g KOH in 100 mL MeOH. There
was then added 8.2 g ethyl bromide, and the mixture held at reflux on
the steam bath. Within 0.5 h, severe bumping ensued. An additional 3
g ethyl bromide were added, refluxing continued for another 0.5 h,
then the reaction mixture was allowed to come to room temperature and
to stand overnight. It was poured into 3 volumes H2O which produced
crystals spontaneously. There was added additional base, and the
mixture was extracted with 3x150 mL CH2Cl2. Removal of the solvent
from the pooled extracts under vacuum gave 6.4 g of
2,4-diethoxyanisole as tan crystals with a mp of 48-48.5 °C.

A mixture of 10.9 g N-methylformanilide and 12.3 g POCl3 was allowed
to stand at room temperature for 0.5 h producing a deep red claret
color. There was then added 6.2 g 2,4-diethoxyanisole and the mixture
was heated on the steam bath for 2 h. All was poured into 200 g
chipped ice, and stirred mechanically. The dark viscous gummy oil
gradually became increasingly granular and finally appeared as
jade-green solids. These were removed by filtration and washed with
H2O, giving a wet cake weighing 18 g and having a mp (from a porous
plate) of 95.5-96.5 °C. The entire crop was recrystallized from 75 mL
boiling MeOH which gave, after filtering, washing lightly with cold
MeOH, and air drying, 5.4 g of 2,4-diethoxy-5-methoxybenzaldehyde with
a mp of 98-99 °C. A solution of 0.2 g of this aldehyde, and 0.3 g
malononitrile in 2.0 mL warm EtOH was treated with a drop of
triethyl-amine. There was an immediate generation of crystals which
were removed by filtration, EtOH-washed, and dried to constant weight.
The bright yellow needles of 2,4-diethoxy-5-methoxybenzalmalononitrile
weighed 0.15 g and had a mp of 172-172.5 °C.

A solution of 5.0 g 2,4-diethoxy-5-methoxybenzaldehyde in 16 g glacial
acetic acid was treated with 2.7 g nitroethane followed by 1.7 g
anhydrous ammonium acetate. The mixture was heated for 2.5 h on the
steam bath, then removed and diluted with a equal volume of H2O. With
cooling there was the generation of a heavy crop of orange crystals
which was removed, washed with 50% acetic acid, and sucked as dry as
possible. The product had a mp of 97-104 °C, and there was
spectrographic evidence of some unreacted starting aldehyde. A small
sample was recrystallized from boiling MeOH, with considerable loss,
to give an analytical sample of
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene as orange-yellow
crystals with a mp of 112-113 °C. Anal. (C14H19NO5) C,H. The
unpurified first crop was employed in the following synthesis of the
corresponding amphetamine.

To a gently refluxing suspension of 2.9 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 4.0 g of impure
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble apparatus
containing the nitrostyrene. This effectively added a warm saturated
solution of the nitrostyrene dropwise over the course of 1 h.
Refluxing was maintained for 5 h and the reaction mixture was cooled
with an external ice bath with the stirring continued. The excess
hydride was destroyed by the cautious addition of 400 mL of 1.5 N
H2SO4. When the aqueous and Et2O layers were finally clear, they were
separated, and 100 g of potassium sodium tartrate was dissolved in the
aqueous fraction. Aqueous NaOH was then added until the pH was above
9, and this was then extracted with 3x150 mL CH2Cl2. Removal of the
solvent under vacuum produced 2.7 g of a pale amber oil that was
dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl
gas. After a few minutes delay, there commenced the separation of
fine white crystals of 2,4-diethoxy-5-methoxyamphetamine hydrochloride
(EEM). After the crystallization was complete, these were removed by
filtration, washed with Et2O and air dried, providing 2.55 g of a fine
white crystalline solid with mp 158-159 °C. Anal. (C14H24ClNO3)
C,H,N.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This particular identity and arrangement of
the alkoxy groups on the amphetamine molecule, EEM, is a totally
unexplored molecule. It is reasonable to assume that it would be way
down in potency, but there is no way of guessing what the nature of
its activity might be at the dosage that would be active.